This invention relates to a novel CETP activity inhibitor which comprises as an active ingredient a compound having a bis-(2-aminophenyl) disulfide structure or a 2-amino-phenylthio structure and more particularly to a pharmaceutical composition for treating or preventing atherosclerosis or hyperlipidemia. This invention also relates to a compound having a bis-(2-aminophehyl) disulfide structure or a 2-aminophenylthio structure, a prodrug compound, a pharmaceutically acceptable salt, hydrates or solvates of these compounds.
From the results of many epidemiological studies, it has been considered that there exists certain relation between atherosclerotic diseases and serum lipoprotein. For example, Badimon et al. (J. Clin. Invest. 85, 1234-1241 (1990)) reported that not only the prevention of development but also regression of atherosclerotic lesions were observed after intravenous injection of fractions containing HDL (high density lipoprotein) and VHDL (very high density lipoprotein) to cholesterol-loaded rabbits. Thus, regarding the relation between atherosclerotic diseases and serum lipoproteins, it is expected that HDL and VHDL may have antiatherosclerotic activity.
Recently, it has been elucidated that there are proteins that transfer lipids among serum lipoproteins, i.e., CETP (cholesterol ester transfer protein). The presence of CETP was first indicated by Nichols and Smith in 1965 (J. Lipid Res. 6, 206 (1965)). cDNA of the protein was later cloned by Drayna et al. in 1987. Molecular weight of the protein as glycoprotein is 74,000 Da. It is about 58,000 Da after complete removal of sugar chain. cDNA of this protein is composed of 1656 nucleotide residues and codes for 476 amino acids following signal peptide of 17 amino acid residues. Since around 44% of these amino acids are hydrophobic, the protein is highly hydrophobic and liable to be inactivated by oxidation. CETP is synthesized in organs like liver, spleen, adrenal, fat tissue, small intestine, kidney, skeletal muscle, and myocardium. It has been confirmed that CETP is synthesized in cells like macrophages derived from human monocytes, B lymphocytes, fat cells, small intestinal epithelial cells, CaCo2 cells, and liver cells (for example, HepG2 cells derived from human hepatoma cells). In addition to these tissues, it is present in cerebrospinal fluid and seminal fluid, too. The presence is also confirmed in culture media of neuroblastoma and neuroglioma cells, and in chorioid plexus of sheep.
It has become apparent that CETP participates in metabolism of all the lipoproteins in vivo and plays important roles in reverse transfer system of cholesterol. It attracted attention as a system that prevents the accumulation of cholesterol into peripheral cells and functions as protective mechanism against atherosclerosis. In relation to HDL, which plays important roles in the reverse transfer system of cholesterol, a great number of epidemiological studies have shown that a decrease in CE (cholesterol esters) of HDL in blood represents one of the risk factors for coronary artery diseases. Activity of CETP differ depending on the species of animals and it has become apparent that cholesterol load does not bring about atherosclerosis in animals with low CETP activity, while it is easily produced in animals with high CETP activity. Absence of CETP results in high HDL-emia+low LDL (low density lipoprotein)-emia and brings about a state resistant to atherosclerosis. Thus, the importance of CETP as mediators of transfer of CE in HDL to blood LDL has become recognized in addition to the importance of HDL in blood.
Free cholesterol (FC) synthesized in the liver and secreted therefrom is taken up into very low density lipoprotein (VLDL). Next, VLDL is metabolized in the blood to LDL via intermediate density lipoprotein (IDL) by the action of lipoprotein lipase (LPL) and liver triglyceride lipase (HTGL). LDL is taken up to peripheral cells mediated by LDL receptor and, thus, FC is supplied to the cells.
Contrary to this flow from the liver to peripheral cells, there exists another flow of cholesterol from peripheral cells to the liver called cholesterol reverse transfer system. FC accumulated in peripheral cells is extracted by HDL, esterified on HDL through the action of LCAT (Lecithin: cholesterol acyltransferase) to form CE, transferred to the hydrophobic core portion of HDL, and HDL becomes matured to globular HDL particles. CE in HDL is transferred to apoB-containing lipoproteins such as VLDL, IDL, and LDL by CETP present in the blood. In exchange, TG is transferred to HDL in mole ratio of 1:1. CE that is transferred to apoB-containing lipoprotein is taken up by the liver via LDL receptor on it and, thus, cholesterol is transferred indirectly to the liver. There is mechanisms, too, by which HDL becomes CE-rich, apoprotein E-containing HDL by taking up apoprotein E secreted by macrophages and the like, which is then taken up directly to the liver via LDL receptor or remnant receptor. In another, the liver cells do not take up HDL particles, but take up selectively only CE in HDL. In still another, HDL particles are taken up by the liver cells via so-called HDL receptor.
In a state, in which CETP activity is augmented, CE in HDL is decreased and CE in VLDL, IDL and LDL is increased due to augmentation of CE transfer from HDL. Increases in uptake of IDL and LDL to the liver result in down-regulation of LDL receptor and increases in LDL in the blood. In contrast, in a state of CETP deficiency, HDL removes cholesterol from peripheral cells with the aid of LCAT, increases its size gradually and acquires apoE. HDL that becomes apoE-rich is taken up by the liver via LDL receptor of the liver and catabolized. However, as the operation of this mechanism is not adequate in the human, retention of large HDL in the blood occurs and, as a result, cholesterol pool in the liver becomes smaller. LDL receptor becomes up-regulated and LDL is decreased.
Hence, by selectively inhibiting CETP, it is possible to decrease IDL, VLDL, and LDL that accelerate atherosclerosis and increase HDL that exhibits inhibitory action. Thus, it is anticipated that hitherto non-existent drugs useful for prevention or therapy of atherosclerosis or hyperlipidemia may be provided.
Very recently there have been reports on chemical compounds that aim at inhibition of such CETP activity.
For example, in Biochemical and Biophysical Research Communications ZZS, 42-47 (1996), dithiodipyridine derivatives and substituted dithiobenzene derivatives are disclosed as compounds capable of inactivating CETP through modification of cysteine residues. However, the literature neither discloses nor suggests the compounds such as those of the present invention which have a bis-(2-aminophenyl) disulfide structure or a 2-aminophenylthio structure.
WO95/06626 discloses Wiedendiol-A and Wiedendiol-B as CETP activity inhibitors, but there is no description suggesting the compounds of the present invention.
Furthermore, in JP-B-Sho 45-11132, JP-B-Sho 45-2892, JP-B-Sho 45-2891, JP-B-Sho 45-2731, and JP-B-Sho 45-2730, mercaptoanilides substituted with higher fatty acids such as o-isostearoylamino thiophenol are disclosed. However, in these publications, the atherosclerosis-preventing action is only referred to and there is no description of test examples that substantiate the action. There is also no description of CETP inhibitory activity. Nor is there description suggestive of compounds of the present invention.
There are several reports on the compounds having a bis-(2-aminophenyl) disulfide structure or a 2-aminophenylthio structure similar to those of the present application of invention.
For example, WO96/09406 discloses disulfide compounds such as 2-acetylaminophenyl disulfide and the like. However, the compounds of the publication are the ones that are useful for retrovirus, i.e., HIV-1, and usefulness as regards inhibitors of CETP activity has not been disclosed. There also is no description suggestive of the usefulness.
In JP-A-Hei 8-253454, diphenyl disulfide compounds such as 2,2xe2x80x2-di(pyrimidylamino)diphenyldisulfide and the like are disclosed. However, the compounds in this publication are the ones that have inhibitory action on production of IL-1xcex2 and on release of TNFxcex1 and there are no disclosure as regards the usefulness as inhibitors of CETP activity. There is even no description suggestive of the usefulness.
In JP-A-Hei 2-155937, bis-(acylaminophenyl) disulfide compounds such as 2,2xe2x80x2-diacetylaminodiphenyl disulfide and the like are disclosed. However, the compounds in this publication relates to the method of making vulcanized rubber filled with carbon black and there are no disclosure as regards the usefulness as inhibitors of CETP activity. There is also no description suggestive of the usefulness. In the claims recited in the publication, C1-C12 cycloalkyl and cycloalkenyl are defined as R9 and R10, and as specific examples cyclohexyl and cyclohexenyl are described. However, in the publication no example that substantiates the use of the compound is shown and there is no description of the general method of production of the compounds.
JP-A-Hei 2-501772 discloses acylamino phenyl disulfide derivatives such as o-pivaloylaminophenyl disulfide and the like as intermediates for production of pyrazolone photocoupler. However, the invention described in this publication relates to the photo-element and not suggestive of the present invention. This publication also describes 2-cyclohexane carbonylamino phenylthio group as an example of coupling-off group of the coupler, but there is no description of examples that substantiate the use of the compound.
JP-A-Hei 8-171167 discloses thiophenol derivatives or disulfide derivatives such as 2-acetylamino thiophenol. However, the invention described in this publication relates to the silver halide emulsion and not suggestive of the present invention.
In JP-A-Hei 4-233908, disulfide derivatives such as bis-(2-acetoamidephenyl) disulfide and the like are disclosed. However, the compounds of this publication is disclosed as chain transfer agents and, thus, the publication does not suggest the present invention. As specific examples of R3 in X,Y, a cyclohexyl group is disclosed, but the example substantiating the use and the general method of production are not described.
JP-A-Sho 63-157150 discloses amidophenyl disulfide derivatives such as o-pivalamidophenyl disulfide and the like as stabilizers. However, the invention of this publication relates to photo-element and is not suggestive of the present invention. In the claim recited in this publication, a cycloalkyl group is defined as R in the substituents V or Y of the stabilizer compounds, but the example substantiating the use and the general method of production are not described.
Bis-(amidophenyl) disulfide derivatives are also disclosed in JP-A-Hei 8-59900, JP-A-Hei 7-258472, JP-A-Hei 7-224028, JP-A-Hei 7-49554, JP-A-Hei 6-19037, JP-A-Hei 6-19024, JP-A-Hei 3-226750, JP-A-Hei 2-284146, JP-A-Hei 2-23338, JP-A-Hei 1-321432, JP-A-Hei 1-278543, and JP-B-Sho 47-357786. However, none of them discloses usefulness as inhibitors of CETP activity and there is no description suggestive of the usefulness.
As described above, the present inventors studied ardently in order to provide the compounds that selectively inhibit CETP activity and, as a result, found compounds useful as novel preventive or therapeutic agents of atherosclerosis or hyperlipidemia with new action mechanism which could increase HDL and at the same time decrease LDL, thereby completing the present invention.
The present invention relates to the compounds and medicaments as shown in the following (1) to (19) which have CETP activity inhibitory effect.
(1) A CETP activity inhibitor comprising as an active ingredient a compound represented by the formula (I): 
wherein
R represents
a straight chain or branched C1-10 alkyl group;
a straight chain or branched C2-10 alkenyl group;
a halo-C1-4 lower alkyl group;
a substituted or unsubstituted C3-10 cycloalkyl group;
a substituted or unsubstituted C1-8 cycloalkenyl group;
a substituted or unsubstituted C3-10 cycloalkyl C10 alkyl group;
a substituted or unsubstituted aryl group;
a substituted or unsubstituted aralkyl group; or
a substituted or unsubstituted 5- or 6-membered heterocyclic group having 1-3 nitrogen, oxygen or sulfur atoms,
X1, X2, X3, and X4 may be the same or different and represents
a hydrogen atom;
a halogen atom;
a C1-4 lower alkyl group;
a halo-C1-4 lower alkyl group;
a C1-4 lower alkoxy group;
a cyano group;
a nitro group;
an acyl group; or
an aryl group,
Y represents
xe2x80x94COxe2x80x94; or
xe2x80x94SO2, and
Z represents
a hydrogen atom; or
a mercapto-protecting group,
a prodrug compound, a pharmaceutically acceptable salt, hydrate, or solvate thereof.
(2) A CETP activity inhibitor comprising as an active ingredient the compound described in the above (1), wherein
R represents
a straight chain or branched C1-10 alkyl group;
a straight chain or branched C2-10 alkenyl group;
a halo-C1-4 lower alkyl group substituted with 1-3 halogen atoms selected from fluorine, chlorine, and bromine;
a C3-10 cycloalkyl group, a C5-8 cycloalkenyl group, or a C3-10 cycloalkyl C1-10 alkyl group, each of which may have 1-4 substituents selected from the group consisting of
a straight chain or branched C1-10 alkyl group,
a straight chain or branched C2-10 alkenyl group,
a C3-10 cycloalkyl group,
a C5-8 cycloalkenyl group,
a C3-10 cycloalkyl C1-10 alkyl group,
an aryl group selected from phenyl, biphenyl, and naphthyl,
an oxo group, and
an aralkyl group having an aryl group selected from phenyl, biphenyl, and naphthyl; or
an aryl, aralkyl, or 5- or 6-membered heterocyclic group with 1-3 nitrogen, oxygen or sulfur atoms, each of which may have 1-4 substituents selected from the group consisting of
a straight chain or branched C1-10 alkyl group,
a straight chain or branched C2-10 alkenyl group,
a halogen atom selected from fluorine, chlorine, and bromine,
a nitro group, and
a halo-C1-4 lower alkyl group having a halogen atom selected from fluorine, chlorine, and bromine;
Z represents
a hydrogen atom;
a mercapto-protecting group selected from the group consisting of
a C1-4 lower alkoxymethyl group,
a C1-4 lower alkylthiomethyl group,
an aralkyloxymethyl group having an aryl group selected from phenyl, biphenyl, and naphthyl,
an aralkylthiomethyl group having an aryl group selected from phenyl, biphenyl, and naphthyl,
a C3-10 cycloalkyloxymethyl group,
a C5-8 cycloalkenyloxymethyl group,
a C3-10 cycloalkyl C10 alkoxymethyl group,
an aryloxymethyl group having an aryl group selected from phenyl, biphenyl, and naphthyl,
an arylthiomethyl group having an aryl group selected from phenyl, biphenyl, and naphthyl,
an acyl group,
an acyloxy group,
an aminocarbonyloxymethyl group,
a thiocarbonyl group, and
a thio group,
a prodrug compound thereof, a pharmaceutically acceptable salt, hydrate, or solvate thereof.
(3) A CETP activity inhibitor comprising as an active ingredient the compound as described in the above (2), which is represented by the formula (I-1): 
wherein R, X1, X2, X3, X4, and Y are the same as in the above (2) and
Z1 represents
a hydrogen atom;
a group represented by the formula 
wherein R, X1, X2, X3, X4, and Y are the same as described above;
xe2x80x94Y1R1,
wherein Y1 represents xe2x80x94COxe2x80x94; or
xe2x80x94CSxe2x80x94, and
R1 represents
a substituted or unsubstituted straight chain or branched C1-10 alkyl group;
a C1-4 lower alkoxy group;
a C1-4 lower alkylthio group;
a substituted or unsubstituted amino group;
a substituted or unsubstituted ureido group;
a substituted or unsubstituted C3-10 cycloalkyl group;
a substituted or unsubstituted C3-10 cycloalkyl C1-10 alkyl group;
a substituted or unsubstituted aryl group;
a substituted or unsubstituted aralkyl group;
a substituted or unsubstituted arylalkenyl group;
a substituted or unsubstituted arylthio group;
a substituted or unsubstituted 5- or 6-membered heterocyclic group having 1-3 nitrogen, oxygen, or sulfur atoms; or
a substituted or unsubstituted 5- or 6-membered heteroarylalkyl group; or
xe2x80x94Sxe2x80x94R2,
wherein R2 represents
a substituted or unsubstituted C1-4 lower alkyl group; or
a substituted or unsubstituted aryl group,
a prodrug compound, a pharmaceutically acceptable salt, hydrate, or solvate thereof.
(4) A CETP activity inhibitor comprising as an active ingredient the compound as described in the above (3), wherein
R1 represents
a straight chain or branched C1-10 alkyl group which may have 1-3 substituents selected from the group consisting of
a halogen atom selected from fluorine, chlorine, and bromine,
a C1-4 lower alkoxy group,
an amino group that may be substituted with a C1-4 lower alkyl, acyl, or hydroxyl group,
a C1-4 lower alkylthio group,
a carbamoyl group,
a hydroxyl group,
an acyl group,
an acyloxy group having an acyl group,
a carboxyl group, and
an aryloxy group that may be substituted with a halogen atom selected from fluorine, chlorine, and bromine;
a C1-4 lower alkoxy group;
a C1-4 lower alkylthio group;
an amino or ureido group that may have 1-2 substituents selected from the group consisting of
a C1-4 lower alkyl group,
a hydroxyl group,
an acyl group, and
an aryl group that may be substituted with a lower C1-4 alkoxy group;
a C3-10 cycloalkyl or C3-10 cycloalkyl C1-10 alkyl group that may have substituents selected from the group consisting of
a straight or branched C1-10 alkyl group,
a C3-10 cycloalkyl group,
a C5-8 cycloalkenyl group,
an aryl group,
an amino group,
a C1-4 lower alkylamino group having a C1-4 lower alkyl group, and
an acylamino group having an acyl group;
an aryl group, an aralkyl group, an arylalkenyl group, or an arylthio group, each of which may have 1-4 substituents selected from the group consisting of
a C1-10 alkyl group,
a halogen atom selected from fluorine, chlorine, and bromine,
a nitro group,
a hydroxyl group,
a C1-4 lower alkoxy group,
a C1-4 lower alkylthio group,
an acyl group,
a halo- C1-4 lower alkyl group having a halogen atom selected from fluorine, chlorine, and bromine, and
an amino group that may be substituted with a C1-4 lower alkyl or acyl group;
a 5- or 6-membered heterocyclic group having 1-3 nitrogen, oxygen or sulfur atoms or a 5- or 6-membered heteroarylalkyl group that may have 1-4 substituents selected from the group consisting of
a straight chain or branched C1-10 alkyl group,
a halogen atom selected from fluorine, chlorine, and bromine,
an acyl group,
an oxo group, and
an halo-C1-4 lower alkyl group having a halogen atom selected from fluorine, chlorine, and bromine; and
R2 represents
a C1-4 lower alkyl group that may have 1-3 substituents selected from the group consisting of
a C1-4 lower alkoxy groups,
an amino group that may be substituted with a C1-4 lower alkyl or acyl group,
a C1-4 lower alkylthio group,
a carbamoyl group,
a hydroxyl group,
a carboxyl group,
an acyl group, and
a 5- or 6-membered heterocyclic group having 1-3 nitrogen, oxygen, or sulfur atoms; or
an aryl group that may have 1-4 substituents selected from the group consisting of
a C1-4 lower alkyl group,
a halogen atom selected from fluorine, chlorine, and bromine,
a nitro group,
a hydroxyl group,
a C1-4 lower alkoxy group,
a C1-4 lower alkylthio group,
an acyl group,
an amino group that may be substituted with a C1-4 lower alkyl or acyl group, and
a halo-C1-4 lower alkyl group having a halogen atom selected from fluorine, chlorine, and bromine,
a prodrug compound, a pharmaceutically acceptable salt, hydrate, or solvate thereof.
(5) A CETP activity inhibitor comprising as an active ingredient the compound as described in the above (1), which is selected from the group consisting of
bis-[2-(pivaloylamino)phenyl] disulfide;
bis-[2-(2-propylpentanoylamino)phenyl]disulfide;
bis-[2-(1-methylcyclohexanecarbonylamino)phenyl] disulfide;
bis-[2-(1-isopentylcyclopentanecarbonylamino)phenyl] disulfide;
bis-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] disulfide;
N-(2-mercaptophenyl)-2,2-dimethylpropionamide;
N-(2-mercaptophenyl)-1-isopentylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-methylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-isopentylcyclopentanecarboxamide;
N-(2-mercaptophenyl)-1-isopropylcyclohexanecarboxamide;
N-(4,5-dichloro-2-mercaptophenyl)-1-isopentylcyclohexanecarboxamide;
N-(4,5-dichloro-2-mercaptophenyl)-1-isopentylcyclopentanecarboxamide;
N-(2-mercapto-5-methylphenyl)-1-isopentylcyclohexanecarboxamide;
N-(2-mercapto-4-methylphenyl)-1-isopentylcyclohexanecarboxamide;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]thioacetate;
S-[2-(1-methylcyclohexanecarbonylamino)phenyl] 2,2-dimethylthiopropionate;
S-[2-(pivaloylamino)phenyl]phenylthioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] 2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] 2-acetylamino-3-phenylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] 3-pyridinethiocarboxylate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] chlorothioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] methoxythioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] thiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] phenoxy-thioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] 2-methylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] 4-chlorophenoxythioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] cyclopropanethiocarboxylate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] 2-acetylamino-4-carbamoylthiobutyrate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] 2-hydroxy-2-methylthiopropionate;
S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl] 2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl] thioacetate;
S-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl] 2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopentylcyclopentanecarbonylamino)-phenyl] 2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)-4-trifluoromethylphenyl] 2,2-dimethylthiopropionate;
O-methyl S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl monothiocarbonate;
S-[2-(1-methylcyclohexanecarbonylamino)phenyl] S-phenyl dithiocarbonate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] N-phenylthiocarbamate;
S-[2-(pivaloylamino)-4-trifluoromethylphenyl] 2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-cyclopropylcyclohexanecarbonylamino) phenyl] 2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(2-cyclohexylpropionylamino)phenyl] 2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-pentylcyclohexanecarbonylamino)-phenyl] 2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-cyclopropylmethylcyclohexane carbonylamino)phenyl] 2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-cyclohexylmethylcyclohexanecarbonylamino)phenyl]2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopropylcyclohexanecarbonylamino)-phenyl] 2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopentylcycloheptanecarbonylamino)-phenyl] 2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopentylcyclobutanecarbonylamino)-phenyl] 2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)-4-nitrophenyl] 2,2-dimethylthiopropionate;
S-[4-cyano-2-(1-isopentylcyclohexanecarbonylamino)phenyl] 2,2-dimethylthiopropionate;
S-[4-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl] 2,2-dimethylthiopropionate;
S-[5-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl] 2,2-dimethylthiopropionate;
S-[4-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl] 2,2-dimethylthiopropionate;
S-[4,5-difluoro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl] 2,2-dimethylthiopropionate;
S-[5-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl] 2,2-dimethylthiopropionate;
bis-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl] disulfide;
2-tetrahydrofurylmethyl 2-(1-isopentylcyclohexanecarbonyl amino)phenyl disulfide;
N-(2-mercaptophenyl)-1-ethylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-propylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-butylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-isobutylcyclohexanecarboxamide;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] cyclohexanethiocarboxylate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] thiobenzoate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] 5-carboxythiopentanoate;
S-[2-(1-isopentylcyclohexanecarbonylamino)-4-methylphenyl] thioacetate;
bis-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl] disulfide;
N-(2-mercaptophenyl)-1-(2-ethylbutyl)cyclohexanecarboxamide;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl] 2-methylthiopropionate;
S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl] 2-methylthiopropionate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl] 1-acetylpiperidine-4-thiocarboxylate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl] thioacetate;
S-[2-[l-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl] 2,2-dimethylthiopropionate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl] methoxythioacetate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl] 2-hydroxy-2-methylthiopropionate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl] 4-chlorophenoxythioacetate;
S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl] 4-chlorophenoxythioacetate; and
S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl]-1-acetyl-piperidine-4-thiocarboxylate,
a prodrug compound, a pharmaceutically acceptable salt, hydrate, or solvate thereof.
(6) A prophylactic or therapeutic agent for hyperlipidemia comprising as an active ingredient the compound as described in the above in (1)-(5), a prodrug compound, a pharmaceutically acceptable salt, hydrate, or solvate thereof.
(7) A prophylactic or therapeutic agent for atherosclerosis comprising as an active ingredient the compound as described in the above in (1)-(5), a prodrug compound, a pharmaceutically acceptable salt, or hydrate or solvate thereof.
(8) A Compound represented by the formula (I-2): 
wherein Rxe2x80x2 represents
a substituted or unsubstituted C3-10 cycloalkyl group or
a substituted or unsubstituted C5-8 cycloalkenyl group;
X1, X2, X3, and X4 are as in the above (1); and
Z1xe2x80x2 represents
a hydrogen atom;
a group represented by the formula: 
wherein Rxe2x80x2, X1, X2, X3, and X4 are as described above;
xe2x80x94Y1R1,
wherein Y1 and R1 are the same as in the above (3) or xe2x80x94Sxe2x80x94R2,
wherein R2 is the same as in the above (3),
a prodrug compound, a pharmaceutically acceptable salt, hydrate, or solvate thereof.
(9) A compound as described above in (8), which is represented by the formula (I-3): 
wherein Rxe2x80x3 represents
a 1-substituted-C3-10 cycloalkyl group or
a 1-substituted-C5-8, cycloalkenyl group;
X1, X2, X3, and X4 are the same as in the above (1); and
Z1xe2x80x3 represents
a hydrogen atoms;
a group represented by the formula: 
wherein Rxe2x80x3, X1, X2, X3, and X, are as described above;
xe2x80x94Y1R1,
wherein Y1 and R1 are the same as in the above (3); or
xe2x80x94Sxe2x80x94R2,
wherein R2 is the same as in the above (3),
a prodrug compound, a pharmaceutically acceptable salt, hydrate, or solvate thereof.
(10) A compound as described in the above (8), which is represented by the formula (II): 
wherein Rxe2x80x2, X1, X2, X3, and X4 are the same as in the above (8), a prodrug compound, a pharmaceutically acceptable salt, hydrate, or solvate thereof.
(11) A compound as described in the above (9), which is represented by formula (II-1): 
wherein Rxe2x80x3, X1, X2, X3, and X4 are the same as in the above (9), a prodrug compound, a pharmaceutically acceptable salt, hydrate, or solvate thereof.
(12) A compound as described in the above (8), which represented by the formula (III): 
wherein Rxe2x80x2, X1, X2, X3, and X4 are the same as in the above (8), a prodrug compound, a pharmaceutically acceptable salt, hydrate, or solvate thereof.
(13) A compound as described in the above (9), which is represented by formula (III-1): 
wherein Rxe2x80x3, X1, X2, X3, and X4 are the same as in the above (9), a prodrug compound, a pharmaceutically acceptable salt, hydrate, or solvate thereof.
(14) A compound as described in the above (8), which is represented by formula (IV): 
wherein Rxe2x80x2, X1, X2, X3, X4, Y1 and R1 are the same as in the above (8), a prodrug compound, a pharmaceutically acceptable salt, hydrate, or solvate thereof.
(15) A compound as described in the above (9), which is represented by formula (IV-1): 
wherein Rxe2x80x3, X1, X2, X3, X4, Y1, and R1 are the same as in the above (9),
a prodrug compound, a pharmaceutically acceptable salt, hydrate, or solvate thereof.
(16) A compound as described in the above (8), which is represented by formula (V): 
wherein Rxe2x80x2, X1, X2, X3, X4, and R2 are the same as in the above (8), a prodrug compound, a pharmaceutically acceptable salt, hydrate, or solvate thereof.
(17) A compound as described in the above (9), which is represented by formula (V-1): 
wherein Rxe2x80x3, X1I X2, X3, X4, and R2 are the same as in the above (9), a prodrug compound, a pharmaceutically acceptable salt, hydrate, or solvate thereof.
(18) A compound as described in the above (8), which is selected from the group consisting of
bis-[2-(1-methylcyclohexanecarbonylamino)phenyl] disulfide;
bis-[2-(1-isopentylcyclopentanecarbonylamino)phenyl]disulfide;
bis-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] disulfide;
N-(2-mercaptophenyl)-1-isopentylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-methylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-isopentylcyclopentanecarboxamide;
N-(2-mercaptophenyl)-1-isopropylcyclohexanecarboxamide;
N-(4,5-dichloro-2-mercaptophenyl)-1-isopentylcyclohexanecarboxamide;
N-(4,5-dichloro-2-mercaptophenyl)-1-isopentylcyclopentanecarboxamide;
N-(2-mercapto-5-methylphenyl)-1-isopentylcyclohexanecarboxamide;
N-(2-mercapto-4-methylphenyl)-1-isopentylcyclohexanecarboxamide;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] thioacetate;
S-[2-(1-methylcyclohexanecarbonylamino)phenyl] 2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] 2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] 2-acetylamino-3-phenylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] 3-pyridinethiocarboxylate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] chlorothioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl]methoxythioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] thiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] phenoxythioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] 2-methylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] 4-chlorophenoxythioacetate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] cyclopropanethiocarboxylate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] 2-acetylamino-4-carbamoylthiobutyrate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] 2-hydroxy-2-methylthiopropionate;
S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl] 2,2-dimethylpropionate;
S-[2-(1-isopentylcyclopentanecarbonylamino)phenyl] thioacetate;
S-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl] 2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopentylcyclopentanecarbonylamino)-phenyl] 2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)-4-trifluoromethylphenyl] 2,2-dimethylthiopropionate;
O-methyl S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] monothiocarbonate;
S-[2-(1-methylcyclohexanecarbonylamino)phenyl] S-phenyl dithiocarbonate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] N-phenylthiocarbamate;
S-[4,5-dichloro-2-(1-cyclopropylcyclohexanecarbonylamino)-phenyl] 2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-pentylcyclohexanecarbonylamino)-phenyl] 2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-cyclopropylmethylcyclohexanecarbonylamino)phenyl] 2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-cyclohexylmethylcyclohexanecarbonylamino)phenyl] 2,2-dimethylthiopropioate;
S-[4,5-dichloro-2-(1-isopropylcyclohexanecarbonylamino)-phenyl] 2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopentylcycloheptanecarbonylamino)-phenyl] 2,2-dimethylthiopropionate;
S-[4,5-dichloro-2-(1-isopentylcyclobutanecarbonylamino)-phenyl] 2,2-dimethylthiopropionate;
S-[2-(1-isopentylcyclohexanecarbonylamino)-4-nitrophenyl] 2,2-dimethylthiopropionate;
S-[4-cyano-2-(1-isopentylcyclohexanecarbonylamino)phenyl] 2,2-dimethylthiopropionate;
S-[4-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl] 2,2-dimethylthiopropionate;
S-[5-chloro-2-(1-isopentylcyclohexanecarbonylamino)phenyl] 2,2-dimethylthiopropionate;
S-[4-fluoro-2-(1-isopentylcyclohexanecarbonylamino)phenyl] 2,2-dimethylthiopropionate;
S-[4,5-difluoro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl] 2,2-dimethylthiopropionate;
S-[5-fluoro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl] 2,2-dimethylthiopropionate;
bis-[4,5-dichloro-2-(1-isopentylcyclohexanecarbonylamino)-phenyl] disulfide;
2-tetrahydrofurylmethyl 2-(1-isopentylcyclohexanecarbonyl-amino)phenyl disulfide;
N-(2-mercaptophenyl)-1-ethylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-propylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-butylcyclohexanecarboxamide;
N-(2-mercaptophenyl)-1-isobutylcyclohexanecarboxamide;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] cyclohexanethiocarboxylate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] thiobenzoate;
S-[2-(1-isopentylcyclohexanecarbonylamino)phenyl] 5-carboxythiopentanoate;
S-[2-(1-isopentylcyclohexanecarbonylamino)-4-methylphenyl] thioacetate;
bis-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl]-disulfide;
N-(2-mercaptophenyl)-1-(2-ethylbutyl)cyclohexanecarboxamide;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl] 2-methylthiopropionate;
S-[2-[1-isobutylcyclohexanecarbonylamino]phenyl] 2-methylthiopropionate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl] 1-acetylpiperidine-4-thiocarboxylate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl] thioacetate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl] 2,2-dimethylthiopropionate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl] methoxythioacetate;
S-[2-[1-(2-ethylbutyl)cyclohexanecarbonylamino]phenyl] 2-hydroxy-2-methylpropionate;
S-(2-[1-[2-ethylbutyl)cyclohexanecarbonylamino]phenyl] 4-chlorophenoxythioacetate;
S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl] 4-chlorophenoxythioacetate; and
S-[2-(1-isobutylcyclohexanecarbonylamino)phenyl] 1-acetylpiperidine-4-thiocarboxylate,
a prodrug compound, a pharmaceutically acceptable salt, hydrate, or solvate thereof.
(19) A phamaceutical composition comprising as an active ingredient the compound as described in the above (8)-(18), a prodrug compound, a pharmaceutically acceptable salt, hydrate, or solvate thereof.
(20) Use of the compound represented by the above formula (I), a prodrug compound, a pharmaceutically acceptable salt, hydrate, or solvate thereof, for production of a CETP activity inhibitor.
(21) Use of the compound represented by the above formula (I), a prodrug compound, a pharmaceutically acceptable salt, hydrate, or solvate thereof, for production of a prophylactic or therapeutic agent for hyperlipidemia.
(22) Use of the compound represented by the above formula (I), a prodrug compound, a pharmaceutically acceptable salt, hydrate, or solvate thereof, for production of a prophylactic or therapeutic agent for atherosclerosis.
(23) A method for inhibition of CETP activity comprising administering to patients the compound represented by the above formula (I), a prodrug compound, a pharmaceutically acceptable salt, hydrate, or solvate thereof.
(24) A method for prevention or therapy of hyperlipidemia comprising administering to patients the compound represented by the above formula (I), a prodrug compound, a pharmaceutically acceptable salt, hydrate, or solvate thereof.
(25) A method for prevention or therapy of atherosclerosis comprising administering to patients the compound represented by the above formula (I), a prodrug compound, a pharmaceutically acceptable salt, or hydrate, or solvate thereof.
The term xe2x80x9cstraight chain or branched C11, alkyl groupxe2x80x9d used herein means an alkyl group having 1-10 carbon atoms which may be straight or branched. Specific examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylbutyl, 2-ethylbutyl, 1-propylbutyl, 1,1-dimethylbutyl, 1-isobutyl-3-methylbutyl, 1-ethylpentyl, 1-propylpentyl, 1-isobutylpentyl, 2-ethylpentyl, 2-isopropylpentyl, 2-tert-butylpentyl, 3-ethylpentyl, 3-isopropylpentyl, 4-methylpentyl, 1,4-dimethylpentyl, 2,4-dimethylpentyl, 1-ethyl-4-methylpentyl, hexyl, 1-ethylhexyl, 1-propylhexyl, 2-ethylhexyl, 2-isopropylhexyl, 2-tert-butylhexyl, 3-ethylhexyl, 3-isopropylhexyl, 3-tert-butylhexyl, 4-ethylhexyl, 5-methylhexyl, heptyl, 1-ethylheptyl, 1-isopropylheptyl, 2-ethylheptyl, 2-isopropylheptyl, 3-propylheptyl, 4-propylheptyl, 5-ethylheptyl, 6-methylheptyl, octyl, 1-ethyloctyl, 2-ethyloctyl, nonyl, 1-methylnonyl, 2-methylnonyl, decyl, and the like groups. A straight chain or branched alkyl group having 1-8 carbon atoms is preferred.
The term xe2x80x9cC1-4 lower alkyl groupxe2x80x9d used herein means an alkyl group having 1-4 carbon atoms, and specifically includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and the like groups.
The term xe2x80x9cstraight chain or branched C2-10 alkenyl groupxe2x80x9d means an alkenyl group having 2-10 carbon atoms with at least one or more double bonds, which may be straight or branched. Specific examples thereof include allyl, vinyl, isopropenyl, 1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-methyl-1-butenyl, crotyl, 1-methyl-3-butenyl, 3-methyl-2-butenyl, 1,3-dimethyl-2-butenyl, 1-pentenyl, 1-methyl-2-pentenyl, 1-ethyl-3-pentenyl, 4-pentenyl, 1,3-pentadienyl, 2,4-pentadienyl, 1-hexenyl, 1-methyl-2-hexenyl, 3-hexenyl, 4-hexenyl, 1-butyl-5-hexenyl, 1,3-hexadienyl, 2,4-hexadienyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1,3-heptadienyl, 2,4-heptadienyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 9-decenyl, and the like groups. An alkenyl group having 2-8 carbon atoms, which may be straight or branched, is preferred.
The term xe2x80x9chalogen atomxe2x80x9d means fluorine, chlorine, and bromine atoms.
The term xe2x80x9chalo-C1-4 alkyl groupxe2x80x9d means the above-described C1-4 lower alkyl group substituted with 1-3 halogens, which may be the same or different. Specific examples thereof include fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, chloroethyl, difluoroethyl, trifluoroethyl, pentachloroethyl, bromopropyl, dichloropropyl, trifluorobutyl, and the like groups. Trifluoromethyl and chloroethyl are preferred.
The term xe2x80x9cC1-4 lower alkoxy groupxe2x80x9d means the alkoxy group containing the C1-4 lower alkyl group as described above. Examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like groups.
The term xe2x80x9cC1-4 lower alkylthio groupxe2x80x9d means the alkylthio group containing the C1-4 lower alkyl group as described above. Examples thereof include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, and the like groups.
The term xe2x80x9cC3-10 cycloalkyl groupxe2x80x9d means a cycloalkyl group having 3-10 carbon atoms, which may be monocyclic or polycyclic. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, octahydroindenyl, decahydronaphthyl, bicyclo[2.2.1 ]heptyl, adamantyl, and the like groups. Preferred are those having 5-7 carbon atoms, including cyclopentyl, cyclohexyl, and cycloheptyl.
The term xe2x80x9cC5-8 cycloalkenyl groupxe2x80x9d means a cycloalkenyl group having 5-8 carbon atoms with one or more double bonds on the ring. Examples thereof include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, cyclooctadienyl, and the like groups. Preferred are those with 5-7 carbon atoms, including cyclopentenyl, cyclohexenyl, and cycloheptenyl.
The term xe2x80x9cC3-10 cycloalkyl C1-10 alkyl groupxe2x80x9d means the above-described straight chain or branched C1-10 alkyl group substituted with the above-described C3-10 cycloalkyl group. Specific examples thereof include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexyl cyclopentylmethyl, dicyclohexylmethyl, 1-cyclopentylethyl, 1-cyclohexylethyl, 2-cyclopropylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, 2-cycloheptylethyl, 1-cyclohexyl-1-methylethyl, 1-cyclohexylpropyl, 2-cyclopentylpropyl, 3-cyclobutylpropyl, 3-cyclopentylpropyl, 3-cyclohexylpropyl, 3-cycloheptylpropyl, 1-cyclopropyl-1-methylpropyl, 1-cyclohexyl-2-methylpropyl, 1-cyclopentylbutyl, 1-cyclohexylbutyl, 3-cyclohexylbutyl, 4-cyclopropylbutyl, 4-cyclobutylbutyl, 4-cyclopentylbutyl, 1-cyclohexyl-1-methylbutyl, 1-cyclopentyl-2-ethylbutyl, 1-cyclohexyl-3-methylbutyl, 1-cyclopentylpentyl, 1-cyclohexylpentyl, 1-cyclohexylmethylpentyl, 2-cyclohexylpentyl, 2-cyclohexylmethylpentyl, 3-cyclopentylpentyl, 1-cyclohexyl-4-methylpentyl, 5-cyclopentylpentyl, 1-cyclopentylhexyl, 1-cyclohexylhexyl, 1-cyclopentylmethylhexyl, 2-cyclopentylhexyl, 2-cyclopropylethylhexyl, 3-cyclopentylhexyl, 1-cyclohexylheptyl, 1-cyclopentyl-1-methylheptyl, 1-cyclohexyl-1,6-dimethylheptyl, 1-cycloheptyloctyl, 2-cyclopentyloctyl, 3-cyclohexyloctyl, 2-cyclopentylmethyloctyl, 1-cyclopentylnonyl, 1-cyclohexylnonyl, 3-cyclopropylnonyl, 1-cyclopentyldecyl, 1-cyclohexylundecyl, 1-cyclopentyltridecyl, 2-cyclohexyltridecyl, and the like groups.
The xe2x80x9caryl groupxe2x80x9d includes phenyl, naphthyl, anthlryl, phenanthryl, biphenyl, and the like groups. Phenyl, naphthyl, and biphenyl groups are preferred.
The xe2x80x9caralkyl groupxe2x80x9d means the above-described C1-4 lower alkyl group substituted with one or more aryl groups as described above. Examples thereof include benzyl, benzhydryl, trityl, phenethyl, 3-phenylpropyl, 2-phenylpropyl, 4-phenylbutyl, naphthylmethyl, 2-naphthylethyl, 4-biphenylmethyl, 3-(4-biphenyl) propyl, and the like groups.
The xe2x80x9carylalkenyl groupxe2x80x9d means an alkenyl group having 2-4 carbon atoms substituted with the above-described aryl group. Examples thereof include 2-phenylvinyl, 3-phenyl-2-propenyl, 3-phenyl-2-methyl-2-propenyl, 4-phenyl-3-butenyl, 2-(1-naphthyl)vinyl, 2-(2-naphthyl)vinyl, 2-(4-biphenyl)vinyl, and the like groups.
The xe2x80x9carylthio groupxe2x80x9d means an arylthio group containing the above-described aryl group and specifically include phenylthio, naphthylthio, and the like groups.
The xe2x80x9cheterocyclic ring groupxe2x80x9d means 5- and 6-membered aromatic or non-aromatic heterocyclic ring groups containing at least one or more, specifically 1-4, preferably 1-3, hetero atoms selected from nitrogen, oxygen, and sulfur atoms. Specific examples thereof include aromatic heterocyclic rings such as thiatriazolyl, tetrazolyl, dithiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, oxazolyl, pyrazolyl, pyrrolyl, furyl, thienyl, tetrazinyl, triazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridyl, or the like groups and non-aromatic heterocyclic rings such as dioxoranyl, pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, dithiadiazinyl, thiadiazinyl, morpholino, morpholinyl, oxazinyl, thiazinyl, piperazinyl, piperidyl, piperidino, pyranyl, thiopyranyl, or the like groups. Preferable groups are aromatic heterocyclic (heteroaryl) groups including furyl, thienyl, pyrrolyl, pyridyl, and the like and non-aromatic heterocyclic groups containing at least one nitrogen atom, including pyrrolidinyl, tetrahydrofuryl, piperazinyl, piperidyl, piperidino, and the like groups.
The xe2x80x9cheteroarylalkyl groupxe2x80x9d means the above-described C1-4 lower alkyl group substituted with the above-described 5- or 6-membered aromatic heterocyclic (heteroaryl) group and specifically include 2-thienylmethyl, 2-furylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 2-thienyl-2-ethyl, 3-furyl-1-ethyl, 2-pyridyl-3-propyl, and the like groups.
The xe2x80x9cacyl groupxe2x80x9d specifically includes formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, acryloyl, propioloyl, metacryloyl, crotonoyl, benzoyl, naphthoyl, toluoyl, hydroatropoyl, atropoyl, cinnamoyl, furoyl, thenoyl, nicotinoyl, isonicotinoyl, glucoloyl, lactoyl, glyceroyl, tropoyl, benzyloyl, salicyloyl, anisoyl, vaniloyl, veratoroyl, piperoniroyl, protocatechoyl, galloyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, 1-methyl cyclohexanecarbonyl, 1-isopentylcyclopentanecarbonyl, 1-isopentyl cyclohexanecarbonyl, tert-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, 2-(1-isopentylcyclohexanecarbonylamino)phenylthiocarbonyl, and the like groups. Preferred are acetyl, tert-butoxycarbonyl, benzoyl, 1-methylcyclohexanecarbonyl, 1-isopentylcyclopentanecarbonyl, 1-isopentylcyclohexanecarbonyl, and 2-(1-isopentylcyclohexanecarbonylamino)phenylthiocarbonyl.
The term xe2x80x9csubstituted or unsubstitutedxe2x80x9d of the xe2x80x9csubstituted or unsubstituted C3-10 cycloalkyl groupxe2x80x9d, the xe2x80x9csubstituted or unsubstituted C5-8 cycloalkenyl groupxe2x80x9d, and the xe2x80x9csubstituted or unsubstituted C3-10 cycloalkyl C1-10 alkyl groupxe2x80x9d described for R, R1, and the like means that the group may be substituted with 1-4 substituents which may be the same or different and any position may be arbitrarily substituted without any limitation. Specific examples of these groups are the above-described straight chain or branched C1-10 alkyl group; the above-described straight chain or branched C2-10 alkenyl group; the above-described C3-10 cycloalkyl group; the above-described C5-8 H cycloalkenyl group; the above-described C3-10 cycloalkyl C1-10 alkyl group; the above-described aryl group; an amino group; a C1-4 lower alkylamino group such as methylamino, ethylamino, or the like groups; an acylamino group such as acetylamino, propionylamino, benzylamino, or the like groups; an oxo group; the above-described aralkyl group; the above-described arylalkenyl group, and the like.
The above substituents are recommended as substituents for R. Among these, preferred for R1 are the above-described straight chain or branched C1-10 alkyl group, the above-described C3-10 cycloalkyl group, the above-described C5-8 cycloalkenyl group, the above-described aryl group, and the above-described amino group.
The term xe2x80x9csubstituted or unsubstituetedxe2x80x9d of the xe2x80x9csubstituted or unsubstitueted aryl groupxe2x80x9d, the xe2x80x9c5- or 6-membered heterocyclic group containing 1-3 nitrogen, oxygen, or sulfur atomsxe2x80x9d, the xe2x80x9csubstituted or unsubstitueted aralkyl groupxe2x80x9d, the xe2x80x9csubstituted or unsubstitueted arylalkenyl groupxe2x80x9d, the xe2x80x9csubstituted or unsubstitueted arylthio groupxe2x80x9d, and the xe2x80x9csubstituted or unsubstitueted 5- or 6-membered heteroarylalkyl groupxe2x80x9d described with respect to R, R1, and the like means that the groups may be substituted with 1-4, preferably 1-3, substituents which may be the same or different and any position may be arbitrarily substituted without particular restriction. Examples of these groups include the above-described straight chain or branched C1-10 alkyl group, preferably a straight chain or branched C1-6 aralkyl group; the above-described straight chain or branched C2-10alkenyl group, preferably a straight chain or branched C2-6 alkenyl group; the above-described halogen atom; a nitro group; the above-described amino group that may be substituted with the above-described C1-4 lower alkyl group or the above-described acyl group; a hydroxyl group; the above-described C1-4 lower alkoxy group; the above-described C1-4 lower alkylthio group; the above-described halo-C1-4 lower alkyl group; the above-described acyl group; an oxo group, and the like.
The above substituents are recommended as substituents mainly for R1. Among these, preferred for R the above-described straight chain or branched C1-6 alkyl group, the above-described halogen atom, and a nitro group.
The xe2x80x9csubstituted or unsubstitutedxe2x80x9d of the xe2x80x9csubstituted or unsubstituted straight chain or branched C1-10 alkyl groupxe2x80x9d described for R, and the like means that the group may be substituted with 1-3 substituents which may be the same or different and any position may be arbitrarily substituted without particular restriction. Examples of these groups are the above-described C1-4 lower alkoxy group; the above-described C1-4 lower alkyl group; the above-described amino group that may be substituted with an acyl or hydroxyl group; the above-described lower C1-4 alkylthio group; a carbamoyl group; a hydroxyl group; the above-described halogen atom; the above-described acyloxy group containing an acyl group; a carboxyl group; the above-described acyl group; the above-described aryloxy group containing an aryl group that may be substituted; and the like.
The xe2x80x9csubstituted or unsubstitutedxe2x80x9d of the xe2x80x9cC1-4 lower alkyl groupxe2x80x9d described with respect to R2 and the like means that the group may be substituted with 1-3 substituents which may be the same or different and any position may be arbitrarily substituted without particular restriction. Examples of the group include the above-described C1-4 lower alkoxy group; the above-described amino group that may be substituted with the above-described C1-4 lower alkyl group or the above-described acyl group; the above-described C1-4 lower alkylthio group; a carbamoyl group; a hydroxyl group; a carboxyl group; the above-described acyl group; the above-described heterocyclic group (particularly aromatic heterocyclic groups such as thienyl or non-aromatic heterocyclic group such as tetrahydrofuryl); and the like.
The term xe2x80x9csubstituted or unsubstitutedxe2x80x9d of the xe2x80x9csubstituted or unsubstituted amino groupxe2x80x9d and the xe2x80x9csubstituted or unsubstituted ureido groupxe2x80x9d described with respect to R, means that the groups may be substituted with one or more, preferably 1-2, substituents which may be the same or different and any position may be arbitrarily substituted without particular restriction. Examples of these groups are the above-described C1-4 lower alkyl group; a hydroxyl group; the above-described acyl group; the above-described aryl group which may be substituted with the above-described C1-4 lower alkoxy group; and the like.
The xe2x80x9cmercapto-protecting groupxe2x80x9d described with respect to z means commonly used mercapto protecting groups. Any organic residues that can be dissociated in vivo may be used without particular restriction. It may form a disulfide structure, that is dimer. Examples thereof include C1-4 lower alkylthiomethyl;C1-4 lower alkylthiomethyl; aralkyloxymethyl;aralkylthiomethyl; C3-10 cycloalkyloxymethyl; C., cycloalkenyloxymethyl; C3-10 cycloalkyl C1-10 alkoxymethyl; aryloxymethyl; arylthiomethyl; acyl; acyloxy; aminocarbonyloxymethyl; thiocarbonyl; and thio groups. Specific examples thereof include a C1-4 lower alkoxymethyl group with the above-described C1-4 lower alkoxy group; a C1-4 lower alkylthiomethyl group with the above-described C1-4 lower alkylthio group; an aralkyloxymethyl group with the above-described aralkyl group; an aralkylthiomethyl group with the above-described aralkyl group; a C3-10 cycloalkyloxymethyl group with the above-described C3-10 cycloalkyl group; a C1-8 cycloalkenyloxymethyl group with the above-described C5-8 cycloalkenyl group; a C3-10 cycloalkyl C1-10alkoxymethyl group with the above-described C3-10 cycloalkyl C1-10 alkyl group; an aryloxymethyl group with the above-described aryl group; an arylthiomethyl group with the above-described arylthio group; an acyl group containing the above-described substituted or unsubstituted straight chain or branched C1-10 alkyl group, the above-described halo-C1-4 lower alkyl group, the above-described C1-4 lower alkoxy group, the above-described C1-4 lower alkylthio group, the above-described substituted or unsubstituted amino group, the above-described substituted or unsubstituted ureido group, the above-described substituted or unsubstituted C3-10 cycloalkyl group, the above-described substituted or unsubstituted C3-10 cycloalkyl C1-10 alkyl group, the above-described substituted or unsubstituted aryl group, the above-described substituted or unsubstituted aralkyl group, the above-described substituted or unsubstituted arylalkenyl group, the above-described substituted or unsubstituted arylthio group, the above-described substituted or unsubstituted 5- or 6-membered heterocyclic group with 1-3 nitrogen, oxygen, or sulfur atoms, or the above-described substituted or unsubstituted 5- or 6-membered heteroarylalkyl group; an acyloxy group containing the above-described substituted or unsubstituted straight chain or branched C1-10 alkyl group, the above-described halo-C1-4 lower alkyl group, the above-described C1-4 lower alkoxy group, the above-described C1-4 lower alkylthio group, the above-described substituted or unsubstituted amino group, the above-described substituted or unsubstituted ureido group, the above-described substituted or unsubstituted C3-10 cycloalkyl group, the above-described substituted or unsubstituted C3-10 cycloalkyl C1-10 alkyl group, the above-described substituted or unsubstituted aryl group, the above-described substituted or unsubstituted aralkyl group, the above-described substituted or unsubstituted arylalkenyl group, the above-described substituted or unsubstituted arylthio group, the above-described substituted or unsubstituted 5- or 6-membered heterocyclic group with 1-3 nitrogen, oxygen, or sulfur atoms, or the above-described substituted or unsubstituted 5- or 6-membered heteroarylalkyl group; an aminocarbonyloxymethyl group that may be substituted with the above-described substituted or unsubstituted straight chain or branched C1-10 alkyl group, the above-described halo-C1-4 alkyl group, the above-described C1-4 lower alkoxy group, the above-described C1-4 lower alkylthio group, the above-described substituted or unsubstituted C3-10 cycloalkyl group, the above-described substituted or unsubstituted C3-10 cycloalkyl C1-10 alkyl group, the above-described substituted or unsubstituted aryl group, the above-described substituted or unsubstituted aralkyl group, the above-described substituted or unsubstituted arylalkenyl group, the above-described substituted or unsubstituted 5- or 6-membered heterocyclic group with 1-3 nitrogen, oxygen, or sulfur atoms, or the above-described substituted or unsubstituted 5- or 6-membered heteroarylalkyl group; a thiocarbonyl group containing the above-described substituted or unsubstituted straight chain or branched C1-10 alkyl group, the above-described halo-C1-4 lower alkyl group, the above-described C1-4 lower alkoxy group, the above-described C1-4 lower alkylthio group, the above-described substituted or unsubstituted amino group, the above-described substituted or unsubstituted ureido group, the above-described substituted or unsubstituted C1-10 cycloalkyl group, the above-described substituted or unsubstituted C3-10 cycloalkyl C1-10 alkyl group, the above-described substituted or unsubstituted aryl group, the above-described substituted or unsubstituted aralkyl group, the above-described substituted or unsubstituted arylalkenyl group, the above-described substituted or unsubstituted arylthio group, the above-described substituted or unsubstituted 5- or 6-membered heterocyclic group with 1-3 nitrogen, oxygen, or sulfur atoms, or the above-described substituted or unsubstituted 5- or 6-membered heteroarylalkyl group; and a thio group containing the above-described substituted or unsubstituted C1-4 lower alkyl or aryl group.
More specifically, preferred as the xe2x80x9cstraight chain or branched C1-10 alkyl groupxe2x80x9d for R are methyl, ethyl, isopropyl, butyl, isobutyl, tert-butyl, heptyl, 1-propylbutyl, and 1-isobutyl-3-methylbutyl.
The xe2x80x9cstraight chain or branched C2-10 alkenyl groupxe2x80x9d referred to as Rare preferably allyl, vinyl, isopropenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-methyl-1-butenyl, crotyl, 1,3-dimethyl-2-butenyl, 1-pentenyl, and 1-methyl-2-pentenyl.
The xe2x80x9chalo-C1-4 lower alkyl groupxe2x80x9d for R means a C1-4 lower alkyl group, particularly preferably a methyl group, substituted with the above-described halogen atom, particularly preferably fluorine and chlorine, with being a trifluoromethyl group preferred.
The xe2x80x9csubstituted or unsubstituted C3-10 cycloalkyl groupxe2x80x9d for R means a C3-10 cycloalkyl group (particularly preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, octahydroindenyl, decahydronaphthyl, adamantyl, andbicyclo[2.2.1]-heptyl) that may be substituted with 1-4 substituents selected from the above-described straight chain or branched C1-10 alkyl group, (particularly preferably a C2-8 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2,2-dimethylpropyl, 4-methylpentyl, 2-ethylbutyl, or the like), the above-described straight chain or branched C2-10 alkenyl group (particularly preferably a C2-8 alkenyl group such as 1-methylvinyl, 2-methylvinyl, 3-methyl-3-propenyl, or the like), the above-described C3-10 cycloalkyl group (particularly preferably a C3-7 cycloalkyl group such as cyclopropyl, cyclopentyl, cyclohexyl, or the like), the above-described C5-8 cycloalkenyl group (particularly preferably a C5-6 cycloalkenyl group such as cyclopentenyl, cyclohexenyl, or the like), the above-described C3-10 cycloalkyl C3-10 alkyl group (particularly preferably a C3-7 cycloalkyl C1-4 alkyl group such as cyclopropylmethyl, 2-cyclopropylethyl, 2-cyclopentylethyl, cyclohexylmethyl, 2-cyclohexylethyl, or the like), the above-described aryl group (particularly preferably a phenyl group), an oxo group, the above described aralkyl group (particularly preferably a phenyl C1-4 lower alkyl group such as benzyl, phenethyl, or the like), and the above-described arylalkenyl group (particularly preferably a 2-phenylvinyl group). Preferable examples thereof include 2,2,3,3-tetramethylcyclopropyl, 1-isopentylcyclobutyl, 1-isopropylcyclopentyl, 1-isobutylcyclopentyl, 1-isopentylcyclopentyl, 1-cyclohexylmethylcyclopentyl, cyclohexyl, 1-methylcyclohexyl, 1-ethylcyclohexyl, 1-propylcyclohexyl, 1-isopropylcyclohexyl, 1-butylcyclohexyl, 1-isobutylcyclohexyl, 1-pentylcyclohexyl, 1-isopentylcyclohexyl, 1-(2,2-dimethylpropyl)-cyclohexyl, 1-(4-methylpentyl)cyclohexyl, 1-(2-ethylbutyl) cyclohexyl, 4-tert-butyl-1-isopentylcyclohexyl, 1-cyclopropylcyclohexyl, 1-bicyclohexyl, 1-phenylcyclohexyl, 1-cyclopropylmethylcyclohexyl, 1-cyclohexylmethylcyclohexyl, 1-(2-cyclopropylethyl) cyclohexyl, 1-(2-cyclopentylethyl)cyclohexyl, 1-(2-cyclohexylethyl)cyclohexyl, 4-methylcyclohexyl, 4-propylcyclohexyl, 4-isopropylcyclohexyl, 4-tert-butylcyclohexyl, 4-pentylcyclohexyl, 4-bicyclohexyl, 1-isopentylcycloheptyl, 3a-octahydroindenyl, 4a-decahydronaphthyl, 1-adamantyl, and 7,7-dimethyl-1-(2-oxo)-bicyclo[2.2.1]heptyl. The site of substitution is not specifically limited, but particularly preferably at position 1. Any substitution group as described above may be used, but the straight chain or branched C1-10 alkyl group is particularly preferred.
The substituent for the xe2x80x9csubstituted or unsubstituted C5-8 cycloalkenyl groupxe2x80x9d for R is the same as that for the above xe2x80x9csubstituted or unsubstituted C3-10 cycloalkyl groupxe2x80x9d. Specifically, it means a cycloalkenyl group (especially cyclopentenyl and cyclohexenyl) that may have 1-4 substituents selected from the above-described straight chain or branched C1-10 alkyl group (particularly preferably a C1-8 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, 2,2-dimethylpropyl, 4-methylpentyl, or the like), the above-described straight chain or branched C2-10 alkenyl group (particularly preferably a C2-8 H alkenyl group such as 1-methylvinyl, 2-methylvinyl, 3-methyl-3-propenyl, and the like), the above-described C3-10 cycloalkyl group (particularly preferably a C3-7 cycloalkyl group such as cyclopropyl, cyclopentyl, cyclohexyl, or the like), the above-described C5-8 cycloalkenyl group (particularly preferably a C5-6 cycloalkenyl group like cyclopentenyl, cyclohexenyl, or the like), the above-described C3-10 cycloalkyl C1-10 alkyl group (particularly preferably a C3-7 cycloalkyl C1-4 lower alkyl group such as cyclopropyl methyl, 2-cyclopropylethyl, 2-cyclopentylethyl, cyclohexylmethyl, 2-cyclohexylethyl, or the like), the above-described aryl group (particularly preferably a phenyl group), an oxo group, the above-described aralkyl group (particularly preferably a phenyl C1-4 lower alkyl group such as benzyl, phenethyl, or the like), and arylalkenyl group (particularly preferably 2-phenylvinyl). Preferable examples of the cycloalkenyl group includes 1-isopropyl-2-cyclopentenyl, 1-isopropyl-3-cyclopentenyl, 1-isobutyl-2-cyclopentenyl, 1-isobutyl-3-cyclopentenyl, 1-isopentyl-2-cyclopentenyl, 1-isopentyl-3-cyclopentenyl, 1-cyclohexylmethyl-2-cyclopentenyl, 1-cyclohexylmethyl-3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-methyl-2-cyclohexenyl, 1-methyl-3-cyclohexenyl, 1-ethyl-2-cyclohexenyl, 1-ethyl-3-cyclohexenyl, 1-propyl-2-cyclohexenyl, 1-propyl-3-cyclohexenyl, 1-isopropyl-3-cyclohexenyl, 1-butyl-2-cyclohexenyl, 1-butyl-3-cyclohexenyl, 1-isobutyl-2-cyclohexenyl, 1-isobutyl-3-cyclohexenyl, 1-pentyl-2-cyclohexenyl, 1-pentyl-3-cyclohexenyl, 1-iso pentyl-2- cyclohexenyl, 1-iso pentyl-3- cyclohexenyl, 1-(2,2-dimethylpropyl)-2-cyclohexenyl, 1-(2,2-dimethylpropyl)-3-cyclohexenyl, 1-(4-methylpentyl)-2-cyclohexenyl, 1-(4-methylpentyl)-3-cyclohexenyl, 1-cyclopropyl-2-cyclohexenyl, 1-cyclopropyl-3-cyclohexenyl, 1-cyclohexyl-2-cyclohexenyl, 1-cyclohexyl-3-cyclohexenyl, 1-phenyl-2-cyclohexenyl, 1-phenyl-3-cyclohexenyl, 1-cyclopropylmethyl-2-cyclohexenyl, 1-cyclo propylmethyl-3-cyclohexenyl, 1-cyclohexylmethyl-2-cyclohexenyl, 1-cyclohexylmethyl-3-cyclohexenyl, 1-(2-cyclopropylethyl)-2-cyclohexenyl, 1-(2-cyclopropylethyl)-3-cyclohexenyl, 1-(2-cyclopentylethyl)-2-cyclohexenyl, 1-(2-cyclopentylethyl)-3-cyclohexenyl, 1-(2-cyclohexylethyl)-2-cyclohexenyl, and 1-(2-cyclohexylethyl)-3-cyclohexenyl. There is no special restriction on the substitution position, but the particularly preferred position is position 1. Any one of the above substituents may be used, but the straight chain or branched C1-10 alkyl group or the C3-10 cycloalkyl C1-4 alkyl group is particularly preferred.
The xe2x80x9csubstituted or unsubstituted C3-10 cycloalkyl C1-10 alkyl groupxe2x80x9d for R means a C3-10 cycloalkyl C1-10 alkyl group (particularly preferably cyclohexylmethyl, 1-cyclohexylethyl, 1-cyclohexyl-1-methylethyl, 1-cyclohexyl-2-methylpropyl, 1-cyclohexyl-3-methylbutyl, 1-cyclohexylhexyl, 1-cyclohexyl-4-methylpentyl, and 1-cyclohexylheptyl) C1-10 alkyl group of which is straight chain or branched and which may have 1-4 substituents selected from the above-described C3-10 cycloalkyl group (particularly preferably a C3-7 cycloalkyl group such as cyclopentyl or cyclohexyl), the above-described C5-8 cycloalkenyl group (particularly preferably a C,-7 cycloalkenyl group such as cyclopentenyl or cyclohexenyl), and the above-described aryl group (particularly preferably a phenyl group). There is no special restriction on the substitution position. The above-described substituents may be placed at the straight chain or branched C1-10 alkyl moiety. Preferable examples of the C3-10 cycloalkyl C1-10 alkyl group include cyclohexylmethyl, 1-cyclohexylethyl, cyclohexylcyclo-pentylmethyl, dicyclohexylmethyl, 1-cyclohexyl-1-methylethyl, 1-cyclohexyl-2-methylpropyl, 1-cyclohexyl-3-methylbutyl, 1-cyclohexyl-4-methylpentyl, 1-cyclohexylhexyl, and 1-cyclohexylheptyl.
The xe2x80x9csubstituted or unsubstituted aryl groupxe2x80x9d for R means an aryl group (particularly preferably a phenyl group) that may have 1-4 substituents selected from the above-described straight chain or branched C1-6 alkyl group (particularly preferably a tert-butyl group), the above-described halogen atom (particularly preferably fluorine and chlorine), and a nitro group. Preferable examples of the aryl group are phenyl, 2-chlorophenyl, 4-nitrophenyl, and 3,5-di-tert-butylphenyl.
The xe2x80x9csubstituted or unsubstituted aralkylxe2x80x9d for R means an aralkyl group (particularly preferably benzyl, benzhydryl, and trityl) which may have substituents selected from the above-described halogen atom (particularly preferably fluorine and chlorine), a nitro group, and a hydroxy group, and in which the C1-4 lower alkyl group is straight chain or branched. There is no special restriction on the position of substitution. The straight chain or branched C1-4 lower alkyl moiety may be substituted. Preferable examples of the aralkyl group are benzyl and trityl.
The xe2x80x9csubstituted or unsubstituted 5- or 6-membered heterocyclic group having 1-3 nitrogen, oxygen or sulfur atomsxe2x80x9d for R means the above-described heterocyclic group that may have 1-4 substituents selected from the above-described straight chain or branched C1-6 alkyl group (particularly preferably a tert-butyl group), the above-described halogen atom (particularly preferably fluorine and chlorine), and a nitro group. The heterocyclic group is preferably an aromatic heterocyclic group, particularly preferably furyl, thienyl, and pyridyl.
The xe2x80x9csubstituted or unsubstituted straight chain or branched C1-10 alkyl groupxe2x80x9d for R, means a straight chain or branched C1-10 alkyl group that may have a substituent selected from the above-described halogen atom (particularly preferably fluorine and chlorine), the above-described C1-4 lower alkoxy group (particularly preferably a methoxy group), an amino group that may be substituted with the above-described C1-4 lower alkyl group (particularly preferably a methyl group), the above-described acyl group (particularly preferably an acetyl group), or a hydroxyl group, the above-described C1-4 lower alkylthio group (particularly preferably a methylthio group), a carbamoyl group, a hydroxyl group, an acyloxy group having the above-described acyl group (particularly preferably an acetyloxy group), a carboxyl group, an acyl group (particularly preferably a methoxycarbonyl group), and an aryloxy group having the above-described substituted or unsubstituted aryl group (particularly preferably a phenoxy group and a 4-chlorophenoxy group). Preferable examples of the alkyl group include methyl, chloromethyl, ethyl, isopropyl, 1-methyl-2-pentyl, octyl, methoxymethyl, dimethylaminomethyl, acetylaminomethyl, 1-acetyl aminoethyl, 1-acetylamino-2-methylpropyl, 1-acetylamino-3-methylbutyl, 1-acetylamino-3-methylthiopropyl, 1-acetylamino-3-carbamoylpropyl, 1-hydroxy-1-methylethyl, 1-acetyloxy-1-methylethyl, 4-carboxybutyl, 2-methoxycarbonylethyl, phenoxymethyl, and 4-chlorophenoxymethyl.
The xe2x80x9cC1-4 lower alkoxy groupxe2x80x9d for R1 is preferably a methoxy group and a tert-butoxy group.
The xe2x80x9cC1-4 lower alkylthio groupxe2x80x9d for R1 is preferably a methylthio group.
The xe2x80x9csubstituted or unsubstituted amino groupxe2x80x9d for R1 means an amino group that may have a substituent selected from the above-described C1-4 lower alkyl group (particularly preferably ethyl, isopropyl, and tert-butyl), the above-described acyl group (particularly preferably acetyl and benzoyl), and the above-described aryl group (particularly preferably phenyl and 4-methoxyphenyl) that may be substituted with the above-described C1-4 lower alkoxy group. Preferable examples of the amino group are ethylamino, isopropylamino, tert-butylamino, phenylamino, and 4-methoxyphenylamino.
The xe2x80x9csubstituted or unsubstituted ureido groupxe2x80x9d for R1 means a ureido group that may have a substituent selected from the above-described C1-4 lower alkyl group (particularly preferably methyl and ethyl), the above-described acyl group (particularly preferably acetyl and benzoyl), and the above-described aryl group (particularly preferably phenyl and 4-methoxyphenyl) that may be substituted with the above-described C1-4 lower alkoxy group, with an N,Nxe2x80x2-diphenylureido group being preferred.
The xe2x80x9csubstituted or unsubstituted C3-10 cycloalkyl groupxe2x80x9d for R1 means a C3-10 cycloalkyl group (particularly preferably cyclopropyl and cyclohexyl) that may have a substituent selected from the above-described straight chain or branched C1-10 alkyl group (particularly preferably methyl, tert-butyl, and isopentyl), an amino group, an amino group (particularly preferably methylamino, ethylamino, acetylamino, and benzylamino) that may be substituted with the above-described C1-4 lower alkyl or acyl groups. Preferable examples the cycloalkyl group are cyclopropyl, cyclohexyl, 1-methylcyclohexyl, 1-isopentylcyclohexyl, 1-aminocyclohexyl, 1-acetylaminocyclohexyl, and 4-tert-butylcyclohexyl.
The xe2x80x9csubstituted or unsubstituted C3-10 cycloalkyl C1-10 alkyl groupxe2x80x9d for R1 means a C3-10 cycloalkyl C1-10 alkyl group which may have a substituent selected from the above-described C3-10 cycloalkyl group (particularly preferably cyclopentyl and cyclohexyl), the above-described C5-8 cycloalkenyl group (particularly preferably cyclopentenyl and cyclohexenyl), and the above-described aryl group (particularly preferably a phenyl group) and in which the C1-10 alkyl moiety is straight chain or branched. There is no special restriction on the position of substitution. The straight chain or branched C1-10 alkyl moiety may be substituted. A cyclohexylmethyl group is preferred as the C1-10 cycloalkyl C1-10 alkyl group.
The xe2x80x9csubstituted or unsubstituted aryl groupxe2x80x9d for R1 means an aryl group (particularly preferably phenyl and naphthyl) that may have a substituent selected from the above-described straight chain or branched C1-6 alkyl group (particularly preferably methyl and tert-butyl group), the above-described halogen atom (particularly preferably fluorine and chlorine), a nitro group, a hydroxyl group, the above-described C1-4 lower alkoxy group (particularly preferably a methoxy group), and the above-described acyl group (particularly preferably a 2-(1-isopentylcyclohexanecarbonylamino)phenylthiocarbonyl group). Preferable examples of the aryl group include phenyl, 1-naphthyl, 2-naphthyl, 2-chlorophenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl, 2-methoxyphenyl, 2-nitrophenyl, 4-nitrophenyl, 3,5-di-tert-butyl-4-hydroxyphenyl, and 4-[2-(1-isopentylcyclohexanecarbonylamino)phenylthiocarbonyl]phenyl.
The xe2x80x9csubstituted or unsubstituted aralkyl groupxe2x80x9d for R1 means an aralkyl group (particularly preferably benzyl, phenethyl, 3-phenylpropyl, naphthylmethyl, and biphenylmethyl) that may have a substituent selected from the above-described halogen atom (particularly preferably fluorine and chlorine), a nitro group, an amino group (particularly preferably amino, acetylamino, pivaloylamino, 1-methylcyclohexanecarbonyl-amino, tert-butoxycarbonylamino, and benzoylamino) that may be substituted with the above-described C1-4 lower alkyl group or the above-described acyl group, and a hydroxyl group, and in which the C1-4 lower alkyl group are straight chain or branched. There is no special restriction on the position of substitution. The straight chain or branched C1-4 lower alkyl moiety may be substituted. Preferable examples of the aralkyl group include benzyl, phenethyl, 3-phenylpropyl, 2-naphthylmethyl, 4-biphenylmethyl, benzhydryl, 2-chlorophenylmethyl, 3-chloro phenylmethyl, 4-chlorophenylmethyl, 2-nitrophenylmethyl, 4-nitrophenylmethyl, 2-pivaloylaminophenylmethyl, 2-(1-methylcyclohexanecarbonylamino)phenylmethyl, 2-tert-butoxy-carbonylaminophenylmethyl, 3-acetylaminophenylmethyl, 3-(1-methylcyclohexanecarbonylamino)phenylmethyl, xcex1-aminobenzyl, xcex1-acetylaminobenzyl, xcex1-(1-methylcyclohexanecarbonylamino)benzyl, xcex1-benzoylaminobenzyl, xcex1-aminophenethyl, xcex1-acetylaminophenethyl, and 1-acetylamino-2-(4-hydorxyphenyl) ethyl.
The xe2x80x9csubstituted or unsubstituted arylalkenyl groupxe2x80x9d for R1 means an arylalkenyl group (particularly phenylvinyl) that may have a substituent selected from the above-described straight chain or branched C1-6 lower alkyl group (particularly preferably methyl and tert-butyl), the above-described halogen atom (particularly preferably fluorine and chlorine), a nitro group, and a hydroxyl group, with a 2-phenylvinyl group being preferred.
The xe2x80x9csubstituted or unsubstituted arylthio groupxe2x80x9d for R1 means an arylthio group (particularly preferably a phenylthio group) that may have a substituent selected from the above-described halogen atom (particularly preferably fluorine and chlorine), a nitro group, and an amino group that may be substituted with the above-described C1-4 lower alkyl group or the above-described acyl group (particularly preferably amino, acetylamino, pivaloylamino, 1-methylcyclohexanecarbonylamino, and benzoylamino), a hydroxyl group, and the above-described halo-C1-4 lower alkyl group (particularly preferably a trifluoromethyl group). Preferably examples of the arylthio group include phenylthio, 2-pivaloylaminophenylthio, 2-(1-methylcyclohexanecarbonylamino)phenylthio, and 2-(1-methyl cyclohexanecarbonylamino-4-trifluoromethyl)phenylthio.
The xe2x80x9csubstituted or unsubstituted 5- or 6-membered heterocyclic ring groups with 1-3 nitrogen, oxygen, or sulfur atomsxe2x80x9d for R1 means heterocyclic ring groups (particularly preferably an aromatic heterocyclic group such as pyridyl or a non-aromatic heterocyclic group such as piperidyl or pyrrolidinyl) that may have substituents selected from the above-described straight chain or branched C1 alkyl group (particularly preferably a methyl group), a halogen atom (particularly preferably fluorine and chlorine), the above-described acyl group (particularly preferably acetyl and benzoyl), and an oxo group. Preferable examples thereof are 3-pyridyl, 1-methyl-4-piperidyl, 1-acetyl-4-piperidyl, 5-oxo-2-pyrrolidinyl, 1-acetyl-2-pyrrolidinyl, and 1-benzoyl-2-pyrrolidinyl. A 4-piperidyl group such as 1-methyl-4-piperidyl or 1-acetyl-4-piperidyl group is particularly preferred.
The xe2x80x9csubstituted or unsubstituted 5- or 6-membered heteroarylalkyl groupxe2x80x9d for R1 means the above-described heteroarylalkyl group (particularly preferably a 2-tenyl group) that may be substituted with the above-described straight chain or branched C1-6 alkyl group (particularly preferably a methyl group) and the above-described halogen atom (particularly preferably fluorine and chlorine). A 2-tenyl group is preferred.
The xe2x80x9csubstituted or unsubstituted C1-4 lower alkyl groupxe2x80x9d for R2 means a C1-4 lower alkyl group (particularly preferably a methyl group) that may have 1-3 substituents selected from the above-described C1-4 lower alkoxy group (particularly preferably a methoxy group), an amino group that may be substituted with the above-described C1-4 lower alkyl or acyl group (particularly preferably a dimethylamino group), the above-described C1-4 lower alkylthio group (particularly preferably a methylthio group), a carbamoyl group, a hydroxyl group, a carboxyl group, the above-described acyl group (particularly preferably a methoxycarbonyl group), and the above-described heterocyclic group (particularly preferably an aromatic heterocyclic group such as thienyl or a non-aromatic heterocyclic group such as tetrahydrofuryl). A tetrahydrofurylmethyl group is preferred.
The xe2x80x9csubstituted or unsubstituted aryl groupxe2x80x9d for R2 is the same as that for R1. Preferable examples thereof are a phenyl group, a halogenated phenyl group, an acylamino-substituted phenyl group, and the like.
The xe2x80x9chalogen atomxe2x80x9d for X1, X2, X3, and X4 means a halogen atom including fluorine, chlorine, bromine, and the like, with fluorine and chlorine being preferred.
The xe2x80x9cC1-4 lower alkyl groupxe2x80x9d for X1, X2, X3, and X4 is preferably a methyl group.
The xe2x80x9chalo-C1-4 lower alkyl groupxe2x80x9d for X1, X2, X3, and X4 means a C1-4 lower alkyl group (particularly preferably a methyl group) substituted with the above-described halogen atom (particularly preferably fluorine and chlorine). A trifluoromethyl group is preferred.
The xe2x80x9cC1-4 lower alkoxy groupxe2x80x9d for X1, X2, X3, and X4, is preferably a methoxy group.
The xe2x80x9cacyl groupxe2x80x9d for X1, X21 X3, and X4 is preferably a benzoyl group.
The xe2x80x9caryl groupxe2x80x9d for X1, X2, X3, and X4 is preferably a phenyl group.
The xe2x80x9c1-substituted-C3-10 cycloalkyl groupxe2x80x9d for Rxe2x80x3 means a cycloalkyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, preferably a C5-7 cycloalkyl group, particularly preferably a cyclohexyl group) that is substituted at position 1 with substituents selected from the above-described straight chain or branched C1-10 alkyl group (particularly preferably a C1-8 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, 2,2-dimethylpropyl, 4-methylpentyl, or 2-ethylbutyl), the above-described straight chain or branched C2-10 alkenyl group (particularly preferably a C2-8 alkenyl group such as 1-methylvinyl, 2-methylvinyl, or 3-methyl-3-propenyl), the above-described C3-10 cycloalkyl (particularly preferably a C3-7 cycloalkyl group such as cyclopropyl, cyclopentyl, or cyclohexyl), the above-described C5-8 cycloalkenyl group (particularly preferably a C., cycloalkenyl group such as cyclopentenyl or cyclohexenyl), the above-described C3-10 cycloalkyl C1-10 alkyl group (particularly preferably a C3-7 cycloalkyl C1-4 lower alkyl group such as cyclopropylmethyl, 2-cyclopropylethyl, 2-cyclopentylethyl, cyclohexylmethyl, or 2-cyclohexylethyl), the above-described aryl group (particularly preferably a phenyl group), the above-described aralkyl group (particularly preferably a phenyl C1-4 lower alkyl group such benzyl and phenethyl), and an arylalkenyl group (particularly preferably 2-phenylvinyl). Preferable examples of the 1-substituted-C3-10 cycloalkyl group include 1-isopentylcyclobutyl, 1-isopropylcyclopentyl, 1-isobutylcyclopentyl, 1-isopentyl cyclopentyl, 1-cyclohexylmethylcyclopentyl, 1-methylcyclohexyl, 1-ethylcyclohexyl, 1-propylcyclohexyl, 1-isopropylcyclohexyl, 1-butylcyclohexyl, 1-isobutylcyclohexyl, 1-pentylcyclohexyl, 1-isopentylcyclohexyl, 1-(2,2-dimethylpropyl)cyclohexyl, 1-(4-methylpentyl)cyclohexyl, 1-(2-ethylbutyl)cyclohexyl, 1-cyclopropylcyclohexyl, 1-bicyclohexyl, 1-phenylcyclohexyl, 1-cyclopropylmethylcyclohexyl, 1-cyclohexylmethylcyclohexyl, 1-(2-cyclopropylethyl)cyclohexyl, 1-(2-cyclopentylethyl)cyclohexyl, 1-(2-cyclohexylethyl)cyclohexyl, and 1-isopentylcycloheptyl. The straight chain or branched C1-10 alkyl group is particularly preferable as a substituent at position 1.
The xe2x80x9c1-substituted-C5-8 cycloalkenyl groupxe2x80x9d for Rxe2x80x3 means a cycloalkenyl groups (particularly preferably a C5-6 cycloalkenyl group such as cyclopentenyl or cyclohexenyl) that is substituted at position 1 with substituents selected from the above-described straight chain or branched C1-10 alkyl group (particularly preferably a C1alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, 2,2-dimethyl propyl, and 4-methylpentyl), the above-described straight chain or branched C2-10 alkenyl group (particularly preferably a C2-8 alkenyl group such as 1-methylvinyl, 2-methylvinyl, or 3-methyl-3-propenyl), the above-described C3-10 cycloalkyl group (particularly preferably a C3-7 cycloalkyl group such as cyclopropyl, cyclopentyl, or cyclohexyl), the above-described C5-8 cycloalkenyl group (particularly preferably a C1-6 cycloalkenyl group such as cyclopentenyl or cyclohexenyl), the above-described C3-10 cycloalkyl C1-10 alkyl group (particularly preferably a C3-7 cycloalkyl C1-4 lower alkyl group such as cyclopropylmethyl, 2-cyclopropylethyl, 2-cyclopentylethyl, cyclohexylmethyl, or 2-cyclohexylethyl), the above-described aryl group (particularly preferably a phenyl group), the above-described aralkyl group (particularly preferably a phenyl C1-4 lower alkyl group such as benzyl or phenethyl), and the above-described arylalkenyl group (particularly preferably a 2-phenylvinyl group). Preferable examples of the 1-substituted-C5-8 cycloalkenyl group include 1-isopropyl-2-cyclopentenyl, 1-isopropyl-3-cyclopentenyl, 1-isobutyl-2-cyclopentenyl, 1-isobutyl-3-cyclopentenyl, 1-isopentyl-2-cyclopentenyl, 1-isopentyl-3-cyclopentenyl, 1-cyclohexylmethyl-2-cyclopentenyl, 1-cyclohexylmethyl-3-cyclopentenyl, 1-methyl-2-cyclohexenyl, 1-methyl-3-cyclohexenyl, 1-ethyl-2-cyclohexenyl, 1-ethyl-3-cyclohexenyl, 1-propyl-2-cyclohexenyl, 1-propyl-3-cyclohexenyl, 1-isopropyl-2-cyclohexenyl, 1-isopropyl-3-cyclohexenyl, 1-butyl-2-cyclohexenyl, 1-butyl-3-cyclohexenyl, 1-isobutyl-2-cyclohexenyl, 1-isobutyl-3-cyclohexenyl, 1-pentyl-2-cyclohexenyl, 1-pentyl-3-cyclohexenyl, 1-isopentyl-2-cyclohexenyl, 1-isopentyl-3-cyclohexenyl, 1-(2,2-dimethylpropyl)-2-cyclohexenyl, 1-(2,2-dimethylpropyl)-3-cyclohexenyl, 1-(4-methylpentyl)-2-cyclohexenyl, 1-(4-methylpentyl)-3-cyclohexenyl, 1-cyclopropyl-2-cyclohexenyl, 1-cyclopropyl-3-cyclohexenyl, 1-cyclohexyl-2-cyclohexenyl, 1-cyclohexyl-3-cyclohexenyl, 1-phenyl-2-cyclohexenyl, 1-phenyl-3-cyclohexenyl, 1-cyclopropylmethyl-2-cyclohexenyl, 1-cyclopropylmethyl-3-cyclohexenyl, 1-cyclohexylmethyl-2-cyclohexenyl, 1-cyclohexylmethyl-3-cyclohexenyl, 1-(2-cyclopropylethyl)-2-cyclohexenyl, 1-(2-cyclopropylethyl)-3-cyclohexenyl, 1-(2-cyclopentylethyl)-2-cyclohexenyl, 1-(2-cyclopentylethyl)-3-cyclohexenyl, 1-(2-cyclohexylethyl)-2-cyclohexenyl, and 1-(2-cyclohexylethyl)-3-cyclohexenyl. The straight chain or branched C1-10 alkyl group is particularly preferable as a substituent at position 1.
The xe2x80x9cprodrug compoundxe2x80x9d means the derivatives of compounds of the present invention having a chemically or metabolically degradable group, which exhibit pharmaceutical activity by degradation through hydrolysis or solvolysis, or under physiological conditions.
The xe2x80x9cpharmaceutically acceptable saltxe2x80x9d means any compound that is an atoxic salt formed with the compound represented by the above formula (I). Examples of such a salt include inorganic acid salts such as hydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates, phosphates, carbonates, bicarbonates, or perchlorates; organic acid salts such as formates, acetates, trifluoroacetates, propionates, tartrates, glycolates, succinates, lactates, maleates, hydroxymaleates, methylmaleates, fumarates, adipiates, tartrates, malates, citrates, benzoates, cinnamates, ascorbates, salicylates, 2-acetoxybenzoates, nicotinates, or isonicotinates; sulfonates such as methane sulfonates, ethane sulfonates, isethionates, benzene sulfonates, p-toluene sulfonates, or naphthalene sulfonates; salts of acidic amino acids such as aspargates or glutamates; alkali metal salts such as sodium salts or potassium salts, alkaline earth metal salts such as magnesium salts or calcium salts; ammonium salts; organic base salts such as trimethylamines, triethylamnes, pyridine salts, picoline salts, dicyclohexylamine salts or N,Nxe2x80x2-dibenzyl ethylenediamine salts; and salts of amino acids such as lysine salts or arginine salts. Depending on the circumstances, hydrates or solvates with alcohols may be used.
More specifically, a 1-isobutylcyclohexyl group, a 1-(2-ethylbutyl) cyclohexyl group, and a 1-isopentylcyclohexyl group are particularly preferable as R in the formula (I), xe2x80x94COxe2x80x94 is particularly preferable as Y, a hydrogen atom is particularly preferable as X1, X2, X3, and X4, and an isobutyryl group and a I-acetyl-4-piperidine carbonyl group are particularly preferable as Z.
The compound of the present invention inhibits CETP activity and is expected as a conventionally unknown, new type of a preventive or therapeutic agent for hyperlipidemia or atherosclerotic diseases.
When used as a pharmaceutical preparation, the compound of the present invention represented by the formula (I) or a pharmaceutically acceptable salt thereof can be usually used together with known pharmacologically acceptable carriers, excipients, diluents, extenders, disintegrators, stabilizers, preservatives, buffers, emulsifiers, aromatics, colorants, sweeteners, viscosity increasing agents, flavor improving agents, solubilizers, and other additives. More specifically, the compound can be formulated into dosage forms, such as tablets, pills, powders, granules, suppositories, injections, eye drops, liquid drugs, capsules, troches, aerosols, elixirs, suspensions, emulsions, or syrup, together with water, plant oil, alcohols such as ethanol or benzyl alcohol, polyethylene glycol, glyceroltriacetate gelatin, lactose, carbohydrates such as starch, magnesium stearates, talc, lanolin, and vaseline, which can be administered orally or parenterally.
The above pharmaceutical preparations contain the compound of the present invention represented by the formula (I) or a pharmaceutically acceptable salt thereof in an amount effective to inhibit CETP activity and prevent or treat hyperlipidemia, atherosclerotic diseases, or the like diseases attributable to CETP activity. One skilled in the art can easily determine such an effective amount.
Doses may vary depending on the type and degree of diseases, the compounds to be administered, the route of administration, the age, sex, and body weight of the patients. In the case of oral administration, it is usually desirable to administer the compound (I) to an adult 1-1000 mg, particularly 50-800 mg per day.
The compound of the present invention can be produced using the following method, but it is needless to say that the method of producing the compound of the present invention is not limited to this method. 
[Step 1]
The compound (II-2) (in the formula R, X1, X2, X3, X4, and Y are as described above) can be synthesized by reacting the compound (VI) (in the formula X1, X2, X3, and X4 are as described above) with the compound (XII) (in the formula X represents a halogen atom and R and Y are as described above) in the presence of a base such as pyridine, triethylamine, N-methylmorpholine, or N-methylpiperazine in an organic solvent such as methylene chloride, chloroform, toluene, ether, tetrahydrofuran, dioxane, diisopropyl ether, dimethoxyethane, or hexane, water, or a mixture of these solvents, or in the absence of a solvent, under cooling through heating temperature.
The compound (III-2) can be synthesized from the compound (II-2) by the following step 2.
[Step 2]
The compound (III-2) (in the formula R, X1, X2, X3, X4, and Y are as described above) can be synthesized by allowing the compound (II-2) (in the formula R, X1, X2, X3, X4, and Y are as described above) to react in the presence of a reducing agent such as sodium borohydride, lithium borohydride, aluminum lithium hydride, triphenylphosphine, zinc, or tin, in an organic solvent such as methanol, ethanol, ether, dioxane, tetrahydrofuran, diisopropyl ether, dimethoxyethane, toluene, hexane, acetone, or acetic acid, water, or a mixture of these solvents, under cooling through heating temperature.
The compound (II-2) or (IV-2) can also be synthesized from the compound (III-2) using the following step 3 or 4.
[Step 3]
The compound (II-2) (in the formula R, X1, X2, X3, X4, and Y are as described above) can be synthesized by allowing the compound (III-2) (in the formula R, X1, X2, X3, X4, and Y are as described above) to react in the presence of an oxidizing agent such as iodine, hydrogen peroxide, potassium permanganate, or dimethylsulfoxide, in an organic solvent such as methanol, ethanol, ether, dioxane, tetrahydrofuran, diisopropyl ether, dimethoxyethane, acetone, toluene, hexane, dimethylformamide, or acetic acid, water, or a mixture of these solvents, or in the absence of a solvent, under cooling through heating temperature.
[Step 4]
The compound (IV-2) (in the formula R, R1, X1, X2, X3, X4, Y, and Y1 are as described above) can be synthesized by reacting the compound (III-2) (in the formula R, X1, X2, X3, X4, and Y are as described above) with acid halide R1xe2x80x94YX (in the formula R1, X, and Y are as described above), isocyanate R1xe2x80x94NY (in the formula R1 and Y are as described above), carbonic halide R1xe2x80x94Oxe2x80x94YX (in the formula R1, X, and Y are as described above), or thiocarbonic halides R1xe2x80x94Sxe2x80x94YX (in the formula R1, X and Y are as described above) in the presence of a base such as pyridine, triethylamine, N-methylmorpholine, or N-methylbipiperazine, in an organic solvent such as methylene chloride, chloroform, toluene, ether, dioxane, tetrahydro furan, diisopropyl ether, dimethoxy ethane, or hexane, water, or a mixture of these solvents, or in the absence of a solvent, under cooling through heating temperature. Alternatively, the compound (IV-2) can be synthesized by reacting the compound (III-2) with carboxylic acid R1xe2x80x94COOH (in the formula R1 is as described above) or thiocarboxylic acid R1xe2x80x94YSH (in the formula R1 and Y are as described above) using a coupling agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, dicyclohexylcarbodiimide, diphenylphosphorylazide, or carbonyldiimidazole, in the presence of an activating agent, if required, such as 1-hydroxybenzotriazole, hydroxysuccinimide, or N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide, in an organic solvent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, dimethylsufoxide, carbon tetrachloride, or toluene, or a mixture of these solvents, under cooling through heating temperature. (The reaction may be carried out in the presence of a base such as pyridine or triethylamine.) Furthermore, the compound (IV-2) can be synthesized by reacting the compound (III-2) with carboxylic acid R1xe2x80x94COOH (in the formula R1 is as described above) in the presence of a base such as triethylamine or pyridine and in the presence of ethyl chlorocarbonate or the like, in a organic solvent such as ethyl acetate or tetrahydrofuran, or a mixture of these solvents, under cooling through heating temperature. When R1 has a carboxyl group, this above step may be conducted using the corresponding ester to obtain the compound by hydrolysis with acid using the known method.
The compound (IV-2) can also be synthesized by subsequently conducting the step 4 following the above step 2 or the step 7 below, or the step 10 below, without isolating the compound (III-2).
The compound (V-2) can be synthesized by conducting the following step 5 or 5xe2x80x2. The step 5 is suitable especially when R2 is the lower alkyl group that may have substituents and the step 5xe2x80x2 is suitable especially when R2 is the aryl group that may have substituents.
[Step 5]
The compound (V-2) (in the formula R, R2, X1, X2, X3, X4, and Y are as described above) can be synthesized by allowing R2xe2x80x94X (in the formula R2 and X is as described above) and a sulfur compound like sodium thiosulfate to react in an organic solvent such as ethanol, methanol, tetrahydrofuran, dioxane, dimethoxyethane, acetone, or acetonitrile, water, or a mixture of these solvents, at room temperature through heating temperature, and adding the compound (III-2) (in the formula R, X1, X2, X3, X4, and Y are as described above) and a basic aqueous solution such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or sodium bicarbonate to the resulting solution under ice-cooling through heating temperature.
[Step 5xe2x80x2]
The compound (V-2) (in the formula R, R2, X1, X2, X3, X4, and Y are as described above) can be synthesized by reacting R2xe2x80x94SH (in the formula R2 is as described above) with trimethylsilane-imidazole in carbon tetrachloride under ice-cooling through room temperature, adding to the resulting solution a reaction mixture resulted from reacting the compound (II-2) (in the formula R, X1, X2, X3, X4, and Y are as described above) with sulfuryl chloride in carbon tetrachloride in the presence of a base such as triethylamine, pyridine, N-methylmorpholine, or N-methylpiperazine under ice-cooling through room temperature, and allowing the resulting mixture to react.
The compound (III-2) can also be synthesized using the following scheme.
[Step 6]
The compound (XI) (in the formula R, X1, X2, X3, X4, and Y are as described above) can be synthesized by reacting the compound (X) (in the formula X1, X2, X3, and X4 are as described above) with the compound (XII) (in the formula R, X, and Y are as described above) in the presence of a base such as pyridine, triethylamine, N-methylmorpholine, or N-methylpiperazine, in an organic solvent such as methylene chloride, chloroform, toluene, ether, dioxane, tetrahydrofuran, diisopropyl ether, dimethoxyethane, or hexane, water, or a mixture of these solvents, or in the absence of a solvent, under cooling through heating temperature.
[Step 7]
The compound (III-2) (in the formula R, X1, X2, X3, X4, and Y are as described above) can be synthesized by allowing the compound (XI) (in the formula R, X1, X2, X3, X4, and Y are as described above) to react in the presence of a base such as sodium acetate, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, or sodium bicarbonate, in an organic solvent such as methanol, ethanol, tetrahydrofuran, dioxane, dimethoxyethane, ether, or diisopropyl ether, water, or a mixture of these solvents, under ice-cooling through heating temperature.
The compound (III-2) can also be synthesized by the following scheme.
[Step 8]
The compound (VIII) (in the formula R11 and R12 may be-the same or different and are a lower alkyl group such as methyl or ethyl, and X1, X2, X3, and X4 are as described above) can be synthesized by reacting the compound (VII) (in the formula X1, X2, X3, and X4 are as described above) with the compound (XIII) (in the formula R11, R12, and X are as described above) in the presence of a base such as sodium hydride, triethylamine, or N-methylmorpholine, in an organic solvent such as dimethylformamide, tetrahydrofuran, dioxane, or dimethoxyethane or a mixture of these solvents, under cooling through heating temperature, and allowing the resulting product to react in an organic solvent such as phenylether or sulfolane or a mixture of these solvents, or in the absence of a solvent, under heating.
[Step 9]
The compound (IX) (in the formula R, R11, R12, X1, X2, X3, X4, and Y are as described above) can be synthesized by allowing the compound (VIII) (in the formula R11, R12, X1, X2, X3, and X4 are as described above) to react in the presence of a reducing agent such as stannous chloride, zinc, iron, sodium dithionite, sodium sulfide, or sodium disulfide, in an organic solvent such as ethyl acetate, acetic acid, methanol, ethanol, tetrahydrofuran, dioxane, diisopropyl ether, dimethoxyethane, or toluene, water, or a mixture of these solvents, under cooling through heating temperature, and reacting the resulting product with the compound (XII) (in the formula R, X, and Y are as described above) in the presence of a base such as pyridine, triethylamine, N-methylmorpholine, or N-methylpiperazine, in an organic solvent such as chloroform, methylene chloride, tetrahydrofuran, ether, dioxane, diisopropyl ether, dimethoxyethane, toluene, or hexane, water or a mixture of these solvents, or in the absence of a solvent, under cooling through heating temperature.
[Step 10]
The compound (III-2) (in the formula R, X1, X2, X3, X4, and Y are as described above) can be synthesized by allowing the compound (IX) (in the formula R, R11, R12, X1, X2, X3, X4, and Y are as described above) to react in the presence of a base such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, or sodium bicarbonate, in an organic solvent such as methanol, ethanol, tetrahydrofuran, dioxane, dimethoxyethane, ether, or diisopropyl ether, water, or a mixture of these solvents, under cooling through heating temperature.
The compound (VI) can also be synthesized from the compound (VIII) by the following step 11.
[Step 11]
The compound (VI) (in the formula X1, X2, X3, and X4 are as described above) can be synthesized by allowing the compound (VIII) (in the formula R11, R12, X1, X2, X3, and X4 are as described above) to react in the presence of a reducing agent such as stannous chloride, zinc, iron, sodium dithionite, sodium sulfide, and sodium disulfide, in an organic solvent such as ethyl acetate, acetic acid, methanol, ethanol, ether, tetrahydrofuran, dioxane, diisopropyl ether, dimethoxyethane, and toluene, water or a mixture of these solvents, under cooling through heating temperature, allowing the resulting product to react in the presence of a base such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, or sodium bicarbonate, in an organic solvents such as methanol, tetrahydrofuran, ethanol, dioxane, ether, diisopropyl ether, or dimethoxyethane, water, or a mixture of these solvents, under cooling through heating temperature, and allowing the product to react in the presence of an oxidizing agent such as iodine, hydrogen peroxide, potassium permanganate, or dimethylsufoxide, in an organic solvent such as methanol, ethanol, ether, dioxane, tetrahydrofuran, diisopropyl ether, dimethoxyethane, acetone, toluene, hexane, dimethylformamide, or acetic acid, water, or a mixture of these solvents, or in the absence of a solvent, under cooling through heating temperature.
The compound (I) thus obtained can be isolated and purified using the known method for separation and purification, such as concentration, concentration under reduced pressure, extraction, crystallization, recrystallization, or chromatography.
The compound of the present invention contains one or more of stereoisomers due to the presence of the asymmetric carbon. Such isomers and mixtures thereof are all included in the scope of the present invention.
In the following the present invention will be described in detail with reference to Examples and Test Example, but the present invention is not limited thereto.